Helicobacter pylori (H. pylori) is a major cause of chronic active gastritis, primary peptic ulcer disease, and is strongly linked to gastric cancer. Individuals infected with H. pylori mount an immune and inflammatory response which fail to clear the infection and may contribute to disease. Despite the inability of the host to clear this infection, we have shown that mice can be protected from H. pylori infection by vaccination. Additionally, challenge of immunized mice induces a significant rise in CD4+ TH1 cell-dependent gastric inflammation that resolves following eradication of the bacteria. Based on studies performed in the previous funding period we have demonstrated that IFNy is the dominant cytokine associated with protective immunity but that IFNy-knockout mice can still be protectively immunized. Significant protection can also be achieved in p35-/- mice (IL-12 knockout mice) although not to the degree of wild type mice. Depletion of p40 however (IL-12/IL-23 double knockout mice) destroys the efficacy of vaccination. Since IL-23-dependent, proinflammatory, IL-17-producing cells (TH-17 cells) have been shown to develop in the absence of IFNy in other models, we hypothesize that immunization primarily results in the development of IL-12-dependent IFNy-producing TH1 cells that promote protective inflammation when recruited to the gastric mucosa in response to H. pylori challenge. Further, either complementary to the IL-12/IFNy pathway or as a compensatory mechanism in the absence of IL-12/IFNy we propose that IL-23-dependent TH-17 cells develop with the potential to promote protective inflammation possibly by recruiting neutrophils to the gastric mucosa following H. pylori challenge. We will explore H. py/or/-associated immunity and pathogenesis in two specific aims designed to 1) determine the roles of IL-12 and IL-23-mediated T cell inflammatory pathways in promoting protective immunity against H. pylori via TH1 and TH-17 mediated pathways, and 2) investigate factors in the gastric mucosa that prevent the activation of these pathways during chronic infection with H. pylori by characterizing the recruitment and retention of regulatory T cells and through genetic analyses designed to identify loci associated with pathogenesis. By studying the inflammation associated with protective immunity against H. pylori we hope to elucidate complimentary or compensatory mechanisms that might be confounding the characterization of the protective immune response. A thorough investigation of this immune response would enhance our knowledge of the role that T cells play in promoting beneficial inflammatory pathways, increase our understanding of immunoregulation in the gastrointestinal mucosa, and suggest potential avenues for immunotherapy (including enhanced vaccines) for the treatment H. pylori infection, inflammatory bowel diseases, and other pathologies associated with the gut.